Objective:

A major objective of our research is to delineate the cell autonomous mechanisms that are responsible for adverse cellular dysfunction in response to various stress conditions, which contribute to neurovascular toxicity and tissue pathogenesis. To further delineate the role of cell-cell interactions and study of paracrine mechanisms which maintains the retinal neurovascular integrity, 3D organotypic models that represent the in vivo tissue architecture and organization are essential.

Approach:

Here we propose to develop an organotypic culture of neurovascular system using human induce pluripotent stem cells. These cells will be differentiated to various cellular component of the neurovasculature including endothelial cells, pericytes, and astrocytes. Using defined synthetic matrices, which allow for “biologically driven assembly” of these cells to a neurovascular unit, we will generate organotypic neurovascular culture systems. These cultures will be adapted for high throughput screening of chemicals with unknown toxicity to identify those with adverse effect on formation of capillary networks.

Expected Results:

Our hypothesis is that these compounds will have adverse effects on developmental processes, which depend on angiogenesis. Using our knowledge regarding the intracellular pathways that contribute to neurovascular dysfunction, we will utilize a high content automated imaging system for further analysis of hit compounds identified in a primary toxicity screen. This knowledge will advance our understanding of the cellular and molecular mechanisms and pathways which contribute to neurovascular dysfunction under adverse conditions, and better risk assessment and management of compounds with unknown toxic effects.

Progress and Final Reports:

Main Center Abstract and Reports:

Subprojects under this Center:(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).R835737C001 Liver MAPsR835737C002 Brain MAPsR835737C003 Cancer MAPs: A 3D Organotypic Microfluidic Culture System to Identify Chemicals that Impact Progression and Development of Breast CancerR835737C004 Vascular MAPs: Vascular and Neurovascular Tissue ModelsR835737C005 Pathway Analysis Core

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.